Theories of Everything with Curt Jaimungal - Denis Noble: "GENES ARE NOT THE BLUEPRINT FOR LIFE"

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Starting point is 00:00:48 So that goal to beat your personal best, keep chasing it. Drive your ambition. Mitsubishi Motors. The central dogma of biology has ruled for decades, but what if it's fundamentally flawed? Dennis Noble is a maverick biologist, a fellow of the Royal Society, and a professor at the University of Oxford, who spent his career challenging the fundamental assumptions of modern genetics. From pioneering computer models in

Starting point is 00:01:19 biology in the 1960s to his current crusade against gene-centric biology. Noble has never shied away from overturning scientific orthodoxy. I'm Kurt Jaimungal, and in this lecture for my series on rethinking the foundations, Noble makes the case that our understanding of life and evolution is due for a radical overhaul, one that could revolutionize medicine and reshape our view of what it means to be human. Professor Dennis Noble, you're one of the pioneers of systems biology at Oxford University. And also along with your collaborator Shapiro, you've spawned a concept called the third way of evolution

Starting point is 00:02:06 Which we'll discuss in the subsequent Q&A For those of you who are watching this is a presentation by professor Dennis Noble for the series here called Rethinking the foundations of biology what lies beyond Darwin Dennis Noble will be giving the inaugural talk, and I'm almost uniformly going to shut my mouth for the next 30 minutes. And in the second video, which is linked in the description, we'll delve into the material from this one

Starting point is 00:02:35 in the format of a podcast. Take it away, Professor. Well, thank you very much, Kurt. It's a pleasure to come onto your series and rethinking the foundations of biology. I love that title because it's precisely what is implied by the title I've used for this. Genes are not the blueprint for life. You can hardly reinvent the foundations of biology with a more dramatic title than to show that it doesn't just come from the genome. But that is in practice what I really think is the case. Now I chose that title partly because in February of this year I was asked by the top science journal,

Starting point is 00:03:30 Nature, to write an article on precisely this title, Genes are not the blueprint for life. And I've also put on this screen not only the Nature page, but also a little book called Understanding Living Systems, which is an attempt in very simple language, lay language, not requiring much technical knowledge at all, the essence of what I'm going to say today in this presentation. So, to give the structure of the talk, I'm going to argue that since genes are not the blueprint of life, measuring them and their association scores with common diseases cannot work. And I will first explain why that is the case. And then by concluding by showing that statistically, it does not in fact succeed even in predicting common diseases.

Starting point is 00:04:36 Interesting. Then the second part of the talk will be, is that approach fails? what is the alternative that may work? And I think the answer is to switch to investigating the functional networks in living organisms that control the genome and controversially enable it to be edited. That is supposed by the modern theory of biology, the modern synthesis, to not be possible. I'm going to show that it is both possible and does happen. And I will then close with two what I think are very encouraging examples to show that medical scientists, particularly physiologists, can achieve that.

Starting point is 00:05:25 But I want to start with just a brief explanation of what the genome is. I'm assuming that the listeners to this program may not be completely familiar with the technical details of what a genome is. It's a very long thin thread of molecules in all of our cells and those molecules are called nucleotides because they reside in the nucleus of our cells. You don't need to know the technical names for them. We just call them A, T, G and C. There are four types and in us humans the genome, that's the total number of these nucleotides

Starting point is 00:06:09 it contains three billion of them that's a figure that will matter in just a moment or two and all of our cells except red blood cells incidentally contain a complete set of the DNA. Now, the important point to make right from the very beginning is that as molecules, chemicals in other words, they can only do what chemicals automatically do. And what we know is they like to connect together, to bind together in pairs. A likes to be with T, G likes to be with C. And in doing this, they have absolutely no choice. They cannot therefore be described as many modern evolutionary biologists do,

Starting point is 00:07:01 as selfish, selfish genes, either metaphorically or literally. Only organisms, you and me, with freedom to choose, can be described sensibly as either selfish or cooperative. And we all know that. When a baby is born, it is not born selfish, it simply has needs. It has a need for food, it has a need for care to enable it to live, grow and flourish. And it only slowly learns that it can choose.

Starting point is 00:07:39 Returning now to the genome, focusing on the sequence of the genome is a little bit like taking the pixels for the message. This is a bit of text from the ending of my little book Understanding Living Systems. We wish them all well. I'll come to that at the end of the presentation. The main point of this part of the presentation is that when we look at a message, if we expand the size of the message sufficiently, all we can see are the individual pixels. The message is no longer clear to us. So I want to ask the question, how did the genome become described as the book of life? Creating us body and mind, as Richard Dawkins would say in his book, The Selfish Gene. Because if that was so, the conditional logic of life would have to be found in the genome. But it's not there. You see, I'm a computer programmer amongst other things because the way I do systems

Starting point is 00:08:53 biology is to model cells, tissues and organs. And I know as a computer programmer that if you look for where all of those conditional expressions are, if this, then that, else something else. If you look for all of those control routines that computer programmers are very familiar with, you won't find them in the genome. Now there are switches in genomes. Every sequence of DNA that is a gene has another little bit of DNA which is its switch. But those switches are controlled by other physiological processes, not by the genome itself. So I ask the question where are life's control routines? Well

Starting point is 00:09:50 they're in our cells because our cells this is a figure showing a complicated diagram of a cell. You don't need to understand the details of the diagram. What you can see though is that it's absolutely packed with structure and that structure is formed from what we call fatty membranes, lipid membranes, with protein channels in them. And those routines that control the genome depend on those protein channels in the lipid membranes. Those are our conditional on-off decision processes and they're sensitive to electrical and chemical processes that we experience in life. Without those membrane processes there could not be choice between various behavioral

Starting point is 00:10:47 options and yet choice is an essential element in any theory as the ability to be either selfish or cooperative. Moreover, all of our nerve cells have these controllable on off switches. So do all the other cells. But now I come to something that may surprise you. There are no genes coding for those membranes. We inherit all of those membrane structures from the egg cell of our mother. Every single one of us depends on that inheritance. There are no genes controlling and forming membranes. Sir, before you move on, do you mind briefly expanding on how membranes come only from the mother and not the genome? The important thing about the membranes in our cells is that there are no genes coding for membranes and yet all of those membrane structures are inherited in the egg cell

Starting point is 00:11:56 of our mother. You see when a sperm with its DNA enters an egg cell, it not only enters the egg cell to fuse its DNA with the DNA from your mother, but it also enters a complete cell from the mother, that is the egg cell, and that contains, just as all other cells in our bodies do, all the membranous structures that get inherited automatically with the egg cell. So when, for example, a couple of years ago Richard Dawkins told me, Dennis, we can keep your DNA for 10,000 years and in 10,000 years we'll be able to recreate you. I said, no, you won't, Richard. And he said, well, why not? I said, where will you find the egg cell from my mother as it was in 1936 when I was born? You see, there's no way we can avoid the fact we inherit the membrane structures and those members structures aware all the control of the genome lies.

Starting point is 00:13:13 No i want to come to some simple proofs that twenty century gene centric biology the idea that jeans are the blueprint for life that they. the idea that genes are the blueprint for life, that they alone can develop into being us, is necessarily wrong. And there are four major dogmas. First is the central dogma of molecular biology. I'll explain that in just a moment. The second is a dogma called the Weismann barrier. Again I'll explain that in a moment. The third dogma is that DNA can replicate itself just like a crystal. And the fourth dogma is that that DNA is separate from its vehicle, that is the cell that carries it. Now just go through these very simply. Centrodogma of molecular biology is in fact a very simple chemical fact that from DNA we make another kind of

Starting point is 00:14:20 nucleotide called RNA and that enables our bodies to make proteins. Proteins are the real driver of activity in living organisms. Now, that's a simple chemical fact. DNA forms RNA that forms proteins. But that simple chemical fact does not prevent the organism editing and changing its genes. What the standard biologist will tell you is, well, it does prevent that because you can't go backwards. You can't go from proteins to make DNA. The point here is that you don't need to. The body knows how to control its genes without that being the case. So, first point, the central dogma of modern evolutionary biology is the Weissmann

Starting point is 00:15:29 barrier. This is the idea introduced over 140 years ago by a geneticist called August Weissmann. It's the idea that the egg cells and sperm cells in the reproductive organs are totally isolated from the rest of the body. So there's no way in which what my body learns during its life can be transmitted to the egg and sperm to form the future generation. Well, I have to tell you that we now know that little molecules, they're called control RNAs, but don't worry about the technical term, little molecules that control the DNA have been shown to communicate body characteristics, like whether your metabolism is this way round or that way round to the germ cells via tiny little packets of molecular information. There is no Weissmann barrier.

Starting point is 00:16:36 It's not able to prevent transmission of information from the body to the egg cell. And are you referring to epigenetics here or something else? Um, good, good point. It is to some extent epigenetic here. So the third, um, major assumption of standard evolutionary biology is that biology is that not only is DNA the source of everything that's needed to create us, it also accurately self-replicates. It doesn't need anything to control that. Well, it's simply not true. It is true. Coming back now to the four types of nucleotide, A will attract T and G will attract C. That is true and that helps the replication of DNA.

Starting point is 00:17:35 But the error rate of that is such that there would be hundreds of thousands of errors in the DNA as one of our cells divides to form two new cells. And what happens is amazing. The cells themselves contain the proteins necessary to cut and paste the DNA and to correct all of those errors. the DNA and to correct all of those errors. So the replication of DNA depends upon that ability of the living cell and only a living cell can do that. And the final fundamental dogma is that the replicator that is DNA is separate from its vehicle which is the cell or if you like our bodies and the fact is since self replication of DNA is impossible in our genomes the replicator cannot be seen as separate from its vehicle. cannot be seen as separate from its vehicle. So the correct interpretation of the molecular biological evidence shows that all of these four fundamental assumptions of modern biology are incorrect. So just to summarize where

Starting point is 00:19:02 I've got to in this part of the talk, living organisms can change their DNA. And incidentally, you and I were experiencing exactly that during the pandemic. How else did our immune systems be able to change the DNA coding for what are called immunoglobulins, that's a long technical term, the part of our immune system that grabs the virus and neutralizes it, how is it possible for the immune system to do that? It's because the immune system, like other systems in our body, is capable of changing the DNA. It actually creates millions of new possible shapes for that protein that captures the virus. So we know that organisms can change their DNA and the central dogma clearly does not prevent that. And as I said, this is precisely

Starting point is 00:20:01 what was happening during the pandemic. Second major point in the summary here is that DNA itself is not a self-replicator. It needs the living cell to do that. And the third take-home message from this part of the talk is that body characteristics can be communicated to the germline that is the future eggs and sperm and via small particles that transmit from the body to Those cells the Weissman barrier therefore is not really a barrier Now why is this all important? It's important to you and me because all important. It's important to you and me because the great promise 30 years ago when the Human Genome Project was launched was that genome sequencing would deliver the goods that matter, new medical treatments. The idea was very

Starting point is 00:21:00 simple, find the gene variant causing the disease, then replace or delete it. Has that happened? No. It's an embarrassing answer with the exception of some rare monogenetic diseases. Those are diseases where a single gene can cause the disease. That is true though only in about 5% of humans. The promise before genome sequencing was that the big scourges of mankind, cancer, diabetes, obesity, heart disease, vascular disease, the various forms of dementia, would all be solved within 10 years of full genome sequencing.

Starting point is 00:21:47 Francis Collins, who was the head of the National Institutes of Health in the United States and therefore the head of the Genome Project over there, claimed in 1999, nearly 25 years ago now, that within 10 years years and I'm quoting him, human genome sequencing would lead to previously unimaginable insights and from there to the common good, including a new understanding of genetic contributions to human disease and the development of rational strategies for minimizing or preventing disease phenotypes altogether. Well, I have to tell you that the latest study from a major university here in the United

Starting point is 00:22:35 Kingdom, University College London, published in the British Medical Journal just last year shows that the genome does not succeed in predicting cardiovascular disease, cancer and many other forms of disease. Sorry to disappoint Dr. Collins but the great promise of the human genome project has simply not been fulfilled and it's not been fulfilled for the reasons I've already explained in this talk. The foundations of biology are incorrect. It can't be fulfilled. So, cures for those diseases have not been found even 20 years after the first full genome sequencing and it cannot happen in the future. And in fact

Starting point is 00:23:27 the association scores as they're called between the presence and absence of most genes and the incidence of major diseases are generally very low. The way geneticists now interpret that is to say that all genes are involved in life processes. Very few living processes depend on a single gene and those, as I explained earlier, depend and will occur only in a rather small percentage of the population. Most of the time, organisms manage very well, even in the absence of key genes and the proteins that enable them to be made. I showed that as a systems biologist in the% of the rhythm shows only a modest small change in frequency. This is called robustness.

Starting point is 00:24:34 And I want to tell you something very important. Most processes in our living bodies are robust. And thank goodness, if one part of our system fails, something else takes over. Most of the time, the robustness copes with the problem. And robustness just means a resilience to perturbation. So that is you have some grace under pressure. Yes, it is exactly so. It is resilience to perturbation. Absolutely.

Starting point is 00:25:05 So to summarize this part of the talk, DNA sequencing does not reliably predict disease states. That's been shown now quantitatively, statistically, by a very important study from University College London published in a prestigious journal, the British Medical Journal. So why should we bother about what our DNA is? Well, I'll tell you what it can tell you. If you buy your DNA sequence from 23andMe or other genome sequencing companies, it might tell you who you're related to. You might find an unknown relative elsewhere in the world, but don't rely on it to tell you what diseases you're likely to have.

Starting point is 00:25:53 That will just make you get upset and anxious when you're told, well, you've got the gene for this kind of cancer. Nobody can tell you that with confidence that you will get cancer. So, except for those rare monogenetic diseases, the ones where somebody has something like cystic fibrosis, where if you've got the gene variant that generates cystic fibrosis, you will necessarily get it. Apart from those, the genome does not predict what you will die from. Can the genome state a probability though? Can it just say that it increases your chances of getting a certain disease or decreases? Yes, that's a very small degree of probability first point and what the university college london researchers showed is that if you ask the question.

Starting point is 00:27:00 Do we get as many. Do we get as many positive predictions for people as negative predictions for people which is what you do when you do a clinical trial of a drug for example what you expect is that most people will get cured by the drug and if so then it gets to be approved if it fails that test and it makes as many. Wrong predictions as correct predictions then it's obviously not been approved well what the university college london team did was to use that same criterion yes there are some positive predictions. You've got a slightly increased percentage of possibility of getting, say, cancer or heart disease. But the trouble is that in many other individuals, it predicted just the reverse. It would actually reduce the probability. These are the criteria that you use when you test a new chemical produced by a pharmaceutical company. And by that criterion, the Human Genome Project has failed. So, I ask the question, what do we do now?

Starting point is 00:28:19 Well, I think we have to stop focusing on genes. What we need to do is to focus on what actually makes us alive. And incidentally, that's not genes. Genes are bits of dead chemical. What we need to study are the living processes in our bodies. I call those the functional physiological networks. And the study of those is indeed called physiology. I'm a physiology and I try to do this kind of work. And I think what I'm showing in this diagram is that we've left great parts of all of that out. You see, focusing on DNA, RNA and protein, that's the central dogma focus, leaves out

Starting point is 00:29:12 the functional networks and it's those that are sensitive to the environment, sensitive to how we feed ourselves, sensitive to what the climate is doing to us, sensitive to the social interactions that we have. And it's these interactions that epigenetically, as we say, over and above the genome, influence the functional networks. That is how we react to our environment and to the environment of other organisms, those are our social interactions, and therefore that's what we need to study, the functional networks, and can we do it? I'm just going to close with two examples,

Starting point is 00:30:00 they're quite technical but I won't bother with the technical detail. I'll just give you the essence of the point. So, let's first of all get an idea of how big a cell really is and what the problem is for communicating from the environment to the nucleus of a cell. Well, I've got on this slide a map of the United Kingdom with England, their island, their Scotland there. And what I'm going to get across to you is that if I enlarged a single nucleotide to the size of my face, perhaps the size of a golf ball, as we're seeing in this slide, Perhaps the size of a golf ball, as we're seeing in this slide. Then the living cell will be the size of a whole country. If the nucleus were here in Oxford, there it is, I've ringed it, then the surface of the cell would be somewhere up in Scotland. Now I want to tell you cells can communicate the two within seconds and they do that so there's a communication from the surface of the cell to the nucleus via extraordinary what are called tubulins.

Starting point is 00:31:19 Little threads in the cell that go all the way from the surface to the center where the DNA is located, and messages can go along those tubulin threads. It's almost as though the living cell is like a subway, or as we say here in the United Kingdom, the underground or the Metro in France. It's got a network of tunnels, literally tubes. Yeah, I've been to London and there would be delays. Trust me. Now just want to mention two major studies that show that we can identify how activity at the surface of the cell, sensing what the environment is doing, can be communicated to the center and to the DNA. This is a study done by one of my former

Starting point is 00:32:21 collaborators, Dick Chen, worked with me 40 years ago and now working at New York University. And he showed how tiny molecules, calcium as it happens, entering the surface membrane can create a messenger that attaches itself to those molecular motors as they're called and the motor goes along the tubulin thread all the way down to the nucleus and then controls the very gene that needs to be controlled. Takes a few seconds to make that journey. Now for those who are interested in the detail of that on the slide

Starting point is 00:33:02 I've included the reference for those who want to go into the detail. Not surprisingly, the detail is highly technical and you don't want me to go through that in this talk. The second example is from my own university. Scientists working in my own department here under a leading scientist called Anant Parekh. They did it with two surface membrane processes receiving calcium moving into

Starting point is 00:33:35 the cell, two different sites creating two signaling molecules that again travel on those tubulins rapidly to generate changes in the nucleus that change gene expression in the way required. Again, the reference for that for those who want to go into the technical detail is on the slide. But I don't want to bother you with the technical information. It's difficult to understand. So I want to finish this talk with a challenge to the world's scientists. You see, these two groundbreaking discoveries shows that functional tubulin pathways from the surface of a cell to the nucleus exist and they can mediate changes in gene expression. I want to know how can the same kinds of tubulins be used in the same kind of way to change DNA when the immune system changes our DNA or when

Starting point is 00:34:47 our nervous system needs to generate new forms of behavior that respond better to our social interactions. I think I can guess that any scientist who can provide the same kind of evidence for the way in which that process occurs ought to win a Nobel Prize. There's my prediction. That's what I want to do to finish what I'm presenting here. I will just summarize that first that medical scientists are already succeeding in finding the control pathways. We don't need to worry about whether the central dogma prevents that from happening. It clearly happens. DNA can have its activity change, that's changes in gene expression,

Starting point is 00:35:40 and it can also have changes in the DNA itself. Our immune system can do that. And I finish by putting out once again the little review in the top science journal Nature that I published in February of this year entitled, Genes are not the blueprint for life. Not surprisingly, it's had a huge amount of attention because it clearly undermines the basic assumption of modern evolutionary biology and biology generally, that somehow genes are the blueprint for life. And I want to finish with a message for young people, And I want to finish with a message for young people, because I think it will require creative ingenuity to shift the culture away from for the challenges of the 21st century. That will have to include understanding how DNA is controlled.

Starting point is 00:36:52 And you and your colleagues in the younger generations will have plenty of looming signposts to warn you what went wrong. It's a generation that will have to take responsibility for the way in which the earth ecosystems need rescuing, even for our own species to survive. And it will be a generation that faces the challenge of ageing societies, requiring medical science to find solutions to the diseases of old age that do not readily yield to gene-ric solutions since those diseases are what we call multi-factorial. Only an integrative approach that understands those interactions, those networks in living organisms can possibly hope to address those diseases. I finish with the finished statement at the end of my little book, Understanding Living Systems.

Starting point is 00:37:50 It is arguably a challenge, the scale of which human society has never faced before. And we wish them all well. Thank you very much. Thank you, Professor. Wonderful presentation. My pleasure. Firstly, thank you for watching. Thank you for listening. There's now a website, curtjymongle.org, and that has a mailing list. The reason being that large platforms like YouTube, like Patreon, they can disable you for whatever reason, whenever they like. That's just part of the terms of service. Now a direct mailing list ensures that I have an untrammeled communication with you.

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Theories of Everything with Curt Jaimungal - Denis Noble: "GENES ARE NOT THE BLUEPRINT FOR LIFE"

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